Development of therapeutic strategy for NAFLD targeting novel molecules identified through the analysis of genome cohort

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K08869
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Jichi Medical University
• Principal Investigator: Iwamoto Sadahiko 自治医科大学, 医学部, 教授 (10232711)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 脂肪肝 / ゲノムワイド関連解析 / 新規関連遺伝子座 / mTORC1

Outline of Final Research Achievements

Our genome-wide association analysis to explore genetic loci associated with lean NAFLD in the Japanese population suggested a new candidate locus mapped to GPC6 in chr13, which also showed weak association with whole NAFLD. The association signal in GPC6 was suggested to function as a regulatory element for adjacent genes, in which GPR180 was nominated as the most likely locus involved functionally in hepatic lipid levels. Gpr180 knockout mice showed ameliorated hepatic lipid deposition and serum lipid levels. The mTOR signaling pathway was the most plausible pathway for the hepatic lipid accumulation in the results of GSEA analysis of the KO mice. Phosphorylation analysis of the signal proteins also supported the weakened mTORC1 signaling in the Gpr180KO mouse liver. The global inhibitor of mTORC, rapamycin, is ineffective for ectopic lipid accumulation. GPR180 could be a novel therapeutic target for fatty liver and dyslipidemia.

Free Research Field

人類遺伝学

Academic Significance and Societal Importance of the Research Achievements

NAFLDの治療は、通常、最大のリスクファクターである肥満に対して体重管理が先ず行われ、それに繋がる食事療法と運動療法が推奨されている。しかし、肥満もインスリン抵抗性もないlean-NAFLDの治療は、その必要性を含め検討不十分であった。本研究は、ゲノムワイド関連解析を用いた探索から、mTORの関わる複雑なシグナル経路のうちmTORC1経路を選択的に調節することによって脂肪肝を軽減させる新たなターゲット分子を提示できたと考えられる。選択性の低いmTORC阻害薬rapamycinに代わる、新たな薬剤開発に向けて、GPR180阻害薬は重要な候補になる可能性がある。